Continuous twin-screw melt granulation of drug-loaded electrospun fibers

Introduction

The dissolution enhancement of potential new drug candidates remains one of the greatest challenges in the pharmaceutical industry, as the ratio of active pharmaceutical ingredients (APIs) belonging to the Biopharmaceutics Classification System (BCS) II class has increased immensely in the past decades.[1], [2], [3] The dissolution rate of these poorly water-soluble APIs can be improved by preparing amorphous solid dispersions (ASDs), a technique already applied during the formulation of several commercially available pharmaceutical products.[4], [5] A simple yet promising method for ASD production is electrospinning (ES), however, the complicated processing of the electrospun material inhibits the realization of the technology’s full potential.[6] Although ES has some specific requirements, like high voltage or application of organic solvents in the case of solvent ES, it has numerous advantages compared to other solvent-based ASD preparation techniques. Solvent ES can be operated at ambient temperature and atmospheric pressure, requires relatively low solvent and energy usage, and has excellent flexibility as a variety of polymers can be used for production.[7] Moreover, as a continuous formulation technology, its importance is likely to also increase with the current shift towards continuous manufacturing (CM) in the pharmaceutical field.[8].

Although numerous publications investigate the ES process[9], [10], [11] and even explore the scale-up of the technology[12], [13], [14], significantly fewer focus on the formulation of the fibers into applicable pharmaceutical dosage forms. Moreover, in several cases where oral formulation was achieved, nonconventional methods were used for tablet production, which cannot be integrated into the current tablet manufacturing lines, making their industrial application challenging.[15], [16], [17] A more promising direction is to focus on a traditional tableting route (milling followed by homogenization with excipients and tablet pressing) to produce conventional tablets. In these examples in the literature, the electrospun material was blended with numerous excipients to overcome the poor flow and tableting properties, low bulk density and electrostatic charging.[18], [19], [20] It enabled the direct tableting of the material[21], moreover the continuous homogenization with the excipients[22] and continuous tableting[23] were also achieved. This processing course proved to be successful, however the large amount of excipient and thus too large tablet size is a major issue. Besides the economic and environmental costs, the extensive use of excipients and the increased tablet size can decrease patient compliance.

Choosing an alternative processing route by incorporating a granulation step can be more effective. The technology is commonly used in the pharmaceutical industry to improve the flow and compression properties of raw materials: according to the European Public Assessment Reports, the majority of tablet formulation processes incorporate a granulation step.[24], [25] The technology can also be carried out in continuous mode with the use of twin-screw granulation, and thus could be inserted into a CM line.[26] A very promising yet underexamined form of the process, melt granulation has particularly lot of advantages. The technique requires milder operation conditions compared to dry granulation, and the use of solvents can also be avoided, making the process shorter, less energy-consuming, more environmentally friendly, and more applicable to moisture-sensitive APIs than wet granulation. Furthermore, melt granulation has also been reported to lead to a narrower granule size range and improved flow and compaction properties.[27], [28], [29].

Although, according to the best knowledge of the authors, granulation of electrospun materials has never been accomplished before, examples of the granulation of ASDs to improve their properties can be found in the literature. Dry granulation was applied to enhance the flow properties of celecoxib-loaded ASDs[30] and to improve the tabletability of acetate succinate-loaded ASDs[31], both prepared by spray drying. Wet granulation was also successfully used to ease the tableting of ASDs prepared by hot-melt extrusion (with nimodipine as API)[32], agitation granulation (with nilvadipine as API)[33] and fusion method (with diazepam[34] and rofecoxib[35] as APIs). Although both approaches have been successfully used, the mechanical stress during dry granulation,[36] and contact with the solvents during wet granulation[32] can induce amorphous–amorphous phase separation as well as crystallization. In order to avoid these issues, melt granulation was chosen for our system.

The goal of our research was to accomplish the granulation of electrospun material by using melt granulation in continuous mode, a process called twin-screw melt granulation (TSMG). The aim was to improve the flow properties and ease the handling of itraconazole (ITR)-loaded ASDs while also reducing the amount of added excipients without inducing crystalline transformation. Consequently, this work attempted to demonstrate that the flow properties of electrospun fibers can be improved via TSMG while retaining the advantageous dissolution properties of the ASD. Furthermore, as both TSMG and ES are continuous methods, their combination is especially promising, as it easily fits into the current trend of CM in the pharmaceutical industry.

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Materials

ITR (a drug with extremely low aqueous solubility (∼1 ng/mL at pH 7 and ∼ 5 g/mL at pH 1[37], [38]), vinylpyrrolidone-vinyl acetate 6:4 copolymer (PVPVA64), and hydroxypropyl-methyl-cellulose 2910 (HPMC) were provided by Sigma-Aldrich (Burlington, United States). Dichloromethane (DCM), absolute ethanol (EtOH), and 37 w/w% hydrochloric acid (HCl) were supplied from Merck Ltd. (Budapest, Hungary). Lactose monohydrate (GranuLac® 70) was obtained from Meggle Pharma (Wasserburg, Germany). The polyethylene-glycol with a molecular weight of 5000–7000 g/mol (PEG 6000) was purchased from Merck Ltd. (Budapest, Hungary). Crosslinked polyvinylpyrrolidone (Kollidon® CL) was given by BASF (Ludwigshafen, Germany).

Petra Záhonyi, Áron Gábor Müncz, Anna Haraszti, Zsombor Kristóf Nagy, István Csontos, György Marosi, Edina Szabó, Continuous twin-screw melt granulation of drug-loaded electrospun fibers, European Journal of Pharmaceutics and Biopharmaceutics, 2024, 114580, ISSN 0939-6411, https://doi.org/10.1016/j.ejpb.2024.114580.

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